Polysaccharides and their derivatives are widely used in pharmaceutical formulations and, in several cases, they play a fundamental role in determining the release rate from the dosage form. This is desired in those cases where active ingredients only exhibit a small absorption window in the gastrointestinal tract or where a pharmaceutical composition is to be released in the body at a constant rate in a desired time scale.
Rahmouni et al. “Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets” Pharm. Dev. Technol. 4 (2003), pp. 335-348 mentions that cross-linked native high amylose starch has attracted a lot of attention as a controlled release excipient for the preparation of solid dosage forms. This is attributed to the swelling and gel-forming properties of the cross-linked starch matrix controlling the diffusion rate of the drugs.
The same article also reports that hydroxypropylmethylcellulose (HPMC) is a widely used hydrophilic polymer for the preparation of controlled release tablets. For that purpose, Rahmouni et al. evaluate the effect of a binary mixture of HPMC and cross-linked starch on tableting properties and the release kinetics of drugs of different solubilities. The outcome of the study is multiple, but in terms of release rate it was found that the incorporation of 10% HPMC reduces the release rate of poorly and moderately water-soluble drugs, while the release rate of highly water-soluble drugs was rapid both in the presence or absence of HPMC.
EP-A-1.382.331 discloses a pharmaceutical formulation designed for controlled release of active ingredients, wherein the tablet consists of multiple layers, i.e. a layer consisting of erodible and/or gellable and/or swellable hydrophilic polymers and a layer containing the active ingredient to be administered. The first layer acts as a barrier for drug release control, and may include HPMC or carboxymethylcellulose, among various other polymeric substances. In order to arrive at a swellable layer EP-A-1.382.331 exemplifies the use of AcDiSol (FMC Corp. Philadelphia, USA) and Explotab® (Mendel, Carmel, N.Y., USA), which are commercially available as cross-linked sodium carboxymethylcellulose (or croscarmellose sodium) and cross-linked sodium carboxymethyl starch (or sodium starch glycolate) respectively having moderate swelling potential.
WO-A-02/00204 and WO-A-02/070021 provide oral dosage forms for administering antineoplastic agents, where gelling of the gastric retention vehicle composition retain the antineoplastic drug in the patient's stomach. A superdisintegrant such as cross-linked carboxymethyl cellulose sodium, sodium starch glycolate or cross-linked polyvinyl pyrollidone may be used. Again, the SSG is cross-linked, given the fact that it is suggested to use Primojel® or Explotab®.
U.S. Pat. No. 6,500,459 describes a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising a hydrophilic carrier and a hydrodynamic diffusion enhancer. According to its examples, a mixture of HPMC and Explotab® SSG may be used.
WO-A-2004/066981 relates to an oral controlled release pharmaceutical composition comprising metaxalone. It may involve sodium starch glycolate as is commercially available as Explotab® and Primojel®.
WO-A-2004/006904 discloses oral controlled-release dosage forms containing acetaminophen. A list of disintegrants is given, among which Primojel® SSG.
Although some of the foregoing publications do not explicitly mention the SSG to be highly cross-linked, the suggested use of Primojel® or Explotab® inevitably implies that it is highly cross-linked SSG that is strived for in the art. Both Primojel® and Explotab® are used as a reference in the accompanying examples, supporting the invention. WO-A-97/46592 teaches the use of a substantially uncross-linked carboxymethyl starch as an auxiliary agent for retarding drugs release. Although measures are taken to prevent cross-linking during etherification of native starch and subsequent drying, the carboxymethyl starch of WO-A-97/46592 still involves cross-linking to a reasonable extent, due to intermolecular esterification between the carboxyl moieties of carboxymethyl substituents and the remaining hydroxyl moieties of carboxymethyl starch. WO-A-97/46592 does not mention the actual amount of cross-linking. Moreover, the international publication is silent on the slow release properties of the carboxymethyl starch in combination with other excipients.
Outside the field of slow release tableted drugs, cross-linked carboxymethyl starch is widely known for its remarkable efficiency in tablet disintegration and enhanced dissolution of the tablet, and is often incorporated in tablet formulations where accelerated absorption of water is needed to disintegrate the tablet as fast as possible; the function of this type of cross-linked carboxymethyl starch is not to retard drug release.
However, neither the reported controlled release excipients HPMC and carboxymethyl starch, to some extent cross-linked, nor the combination of HPMC and cross-linked carboxymethyl starch give satisfactory slow drug release. Hence, in the art there is a continuous need to further improve the slow release properties of tableted drugs through the choice of excipient(s).